Chromosome 15 ©Chromosome Disorder Outreach Inc. (CDO) Technical genetic content provided by Dr. Iosif Lurie, M.D. Ph.D Medical Geneticist and CDO Medical Consultant/Advisor. Ideogram courtesy of the University of Washington Department of Pathology: ©1994 David Adler.hum_15.gif Introduction Chromosome 15 (as well as chromosomes 13 and 14) is an acrocentric chromosome. Its short arm does not contain any genes. The genetic length of the long arm of chromosome 15 is 81 Mb. It is ~3% of the total human genome. The length of its short arm is ~20 Mb. Chromosome 15 contains from 700 to 1,000 genes. At least 10% of these genes are important for the development of the body plan and sustaining numerous functional activities. There are 2 peculiar characteristics of this chromosome. 1. The structure of some regions of this chromosome (15q11.2 and 15q13.3) is predisposed to a relatively frequent occurrence of microdeletions and microduplications of these areas. Of course, diagnosis of these microanomalies is possible only using sophisticated molecular methods. An increasing amount of evidence regarding the clinical significance of these microanomalies shows that they make a particular niche between “standard” deletions (leading to some defects in all affected persons) and normal variants. Increased frequency of these microanomalies was found in patients with different types of pathology such as: schizophrenia, seizures, obesity, and autism. At the same time, many persons with these abnormalities (including many parents of affected persons) do not have any phenotypic abnormalities. Most likely, these microdeletions have to be considered as “risk factors”, but not the only cause of any type of pathology. 2. Deletions of the paternal and maternal segments 15q11q13 will lead to different clinical consequences. (Usually every individual has one copy of each chromosome inherited from the mother and one copy of this chromosome inherited from the father). The differences in the phenotypic picture of the paternal and maternal deletions are caused by the specific character of the genes in the deleted region. This phenomenon is called “genetic imprinting”. The deletions of the proximal area of 15q are very common: there are more than 1,000 reports about such patients (including patients with microdeletions 15q11.2 and 15q13.3. Deletions of more distal areas are not so common. There are two syndromes caused by deletions of the distal part of 15q: a well–known condition caused by a distal deletion, usually involving the deletion of the IGFR1 gene, and the recently described syndrome caused by del 15q24. This syndrome, delineated only by methods of molecular cytogenetics, has been reported so far only in a couple dozen patients. Deletions of Chromosome 15 Chromosome 15 (as well as chromosomes 13 and 14) is an acrocentric chromosome. Loss of the short arm of chromosome 15 is not associated with any abnormalities. Deletions of the long arm may cause clinical consequences. The genetic length of the long arm of chromosome 15 is ~81 Mb. Loss of the genetic material of the long arm of 15q causes several clinical syndromes. Deletions of 15q11q13 The situation regarding deletions of the segment 15q11q13 is unique, because clinical manifestations of this deletion are different depending on which chromosome 15 (maternal or paternal) is deleted. One chromosome 15 (as well as any other chromosome) in each diploid cell had a maternal origin (it came from an egg–cell), and another chromosome 15 had a paternal origin (it came from a sperm). If the segment 15q11q13 is lost from the paternal chromosome 15, the patient develops Prader–Willi syndrome. If the same segment is lost from the maternal chromosome 15, the patient will have Angelman syndrome. The phenomenon of the parent–specific function of the genes within any chromosomal segment is called genomic imprinting. There are some other examples of imprinting regarding manifestations of chromosomal pathology in humans (e.g. partial trisomy 11p15 will have different clinical consequences depending on the parent whose chromosome 11p is duplicated), but deletion 15q11q13 is the most frequent and best studied example of genomic imprinting in human chromosomal pathology. The following are descriptions of the two syndromes caused by this deletion and genomic imprinting: • Prader–Willi Syndrome The genetic basis of the syndrome is a loss (or un–expression) of the small group of genes within 15q11q13. The patient will have manifestations of this disorder only if the deletion (or the inactivation) occurred within the chromosome 15 inherited from the father. Clinically Prader–Willi syndrome (PWS) is known from the 1950’s, but its etiology became known only in the early 1980’s. PWS occurs relatively frequently. At least 1:20,000 live born infants will develop this condition. The patients with PWS usually do not have congenital malformations, but there is a complex of mostly functional defects, which allows the recognition of this syndrome even before cytogenetic examination. The babies are very floppy (hypotonic). Sometimes reduced fetal movements are even mentioned during pregnancy. The newborn babies are very sleepy. Hypogonadism may be evident even in newborn boys. The infants continue to be floppy and sleepy. A delay of psycho–motor development may be noticed already at that stage: infants start sitting, standing, crawling, and walking later than healthy infants of the same age. Delay in speech development is one of most common signs of PWS. Hyperphagia (over–eating, sometimes with insatiable appetite) becomes evident usually starting from 3–4 years. As a result of over–eating and relatively low physical activity, most children become obese. Scoliosis develops in a significant number of children. Facial characteristics of the syndrome include elongated face, prominent nasal bridge, thin down–turned lips. Obesity persists in the adolescent period and in adulthood. Frequent striae are a direct result of obesity and soft skin. Hypogonadism affects both sexes. While a small size of the testicles is evident even in small boys, hypogonadism in girls becomes obvious only in adulthood as late onset of menstrual periods or amenorrhea. Hormone replacement therapy may be necessary. A delay in psycho–motor development in most patients is mild or moderate. Severe intellectual defects (as well as almost normal intellectual development) are relatively rare. A cognitive profile of these patients includes relatively good spatio–visual orientation, reading and vocabulary, but serious problems with spoken language. 5– 10% of adult patients reveal hallucinations, paranoia or depression. Deletions of the paternal copy of 15q11q13 are the most common. Other mechanisms include uniparental disomy (if both copies of the 15q11q13 region in a patient are maternal) or translocations with breaks in the area of 15q11q13. Clinical diagnosis of PWS has to be confirmed by cytogenetic examinations. It should be noted that patients with terminal deletions of 2p (2p25–pter) and with interstitial deletions of 6q16 may have very similar clinical manifestations. • Angelman syndrome Loss of the maternal copy of 15q11q13 leads to Angelman syndrome (AS). Prevalence of this syndrome is approximately the same as the prevalence of PWS: about 1:20,000 newborns. Although AS was described in the 1960’s, this condition was practically unknown until the 1980’s when cytogenetic examinations showed the deletion of 15q11q13 in patients with this condition. Basically, it was shown that the absence (or mutation) of the maternal UBE3A gene is crucial for the development of the syndrome. Clinical manifestations of AS include intellectual disability, speech impairment and ataxia. Developmental delay, in most patients very significant, is an obligate manifestation of the syndrome. The patients do not speak at all or have very limited use of words, although non–verbal communication is much better than verbal. All patients with AS have ataxia (disturbance of balance). Most children develop epilepsy and microcephaly (usually after 2 years). Severe delay in psycho–motor development, almost absent speech and ataxia are associated with a happy excitable demeanor, usually with frequent laughter, almost constant smiling, frequent hand flapping (when H. Angelman described this condition in 1965 he used a term “happy puppet syndrome. Now, this term is used in very rare publications). External features: hypopigmented skin and eyes, strabismus, wide mouth and prominent mandible are common, but not characteristic enough to make a diagnosis by photo (as it can be done for many other syndromes). Sexual development is basically non–affected. Defects of internal organs are not characteristic. Diagnosis is based upon an association of tremor, jerky limb movements, wide–based gait, frequent laughter and epilepsy. Only symptomatic treatment of seizures is possible. Both variants of del 15q11q13 are relatively common. There are special support groups both for the families with PWS and for the families with AS. Deletions of 15q11.2 and 15q13.3 The wide use of array–CGH helped find tiny deletions in two specific regions of chromosome 15 — 15q11.2 and 15q13.3. These microdeletions are relatively frequent. For the last 3–4 years, del 15q11.2 were reported in ~40 persons and del 15q13.3 in ~160. Both of these deletions share one common characteristic. Usually (at the molecular level), breakpoints in different patients with apparently the same deletion are different. This is not so for the above– mentioned